IMA901: a multi-peptide cancer vaccine for treatment of renal cell cancer

Abstract

Despite a major improvement in the treatment of advanced kidney cancer by the recent introduction of targeted agents such as multi-kinase inhibitors, long-term benefits are still limited and a significant unmet medical need remains for this disease. Cancer immunotherapy has shown its potential by the induction of long-lasting responses in a small subset of patients, however, the unspecific immune interventions with (high dose) cytokines used so far are associated with significant side effects. Specific cancer immunotherapy may circumvent these problems by attacking tumor cells while sparing normal tissue with the use of multi-peptide vaccination being one of the most promising strategies. We here summarize the clinical and translational data from phase I and II trials investigating IMA901. Significant associations of clinical benefit with detectable T cell responses against the IMA901 peptides and encouraging survival data in treated patients has prompted the start of a randomized, controlled phase III trial in 1st line advanced RCC with survival results expected toward the end of 2015. Potential combination strategies with the recently discovered so-called checkpoint inhibitors are also discussed.

Keywords: 5-FU, 5 fluorouracil; AE, Adverse event; CTL, Cytotoxic T-lymphocyte; CY, Cyclophosphamide; Cancer vaccine; DC, Dendritic cell; DCR, Disease control rate; ECG, Electrocardiogram; ELISpot, Enzyme-linked immunospot assay; FDA, Food and Drug Administration; GM-CSF; HBV, Hepatitis B virus; HLA, Human leukocyte antigen; IFN, Interferon; IL, Interleukin; IMA901; MDSC, Myeloid-derived suppressor cells; MHC, Major histocompatibility complex; MSKCC, Memorial Sloan Kettering Cancer Center; NCI-CTC, National Cancer Institute-Common Toxicity Criteria; OS, Overall survival; PD, Progressive disease; PFS, Progression-free survival; PK, Pharmacokinetic; PR, Partial response; RCC, Renal cell carcinoma; RECIST, Response Evaluation Criteria in Solid Tumors; SAE, Serious adverse event; SD, Stable disease; TKI, Tyrosine-kinase inhibitors; TNF, Tumor necrosis factor; TUMAP, Tumor-associated peptides; Tregs, Regulatory T-cells; VEGF, Vascular endothelial growth factor; ccRCC, Clear cell renal cell carcinoma; checkpoint inhibitor; cyclophosphamide; i.d., intradermal; immunotherapy; intradermally; kidney cancer; mRNA, Messenger ribonucleic acid; mTOR, Mammalian target of rapamycin; mg, Milligram; n, Number; renal cell carcinoma; s.c., subcutaneous, subcutaneously; tumor-associated peptides; vaccination; μg, Microgram.

Figure 1.

Vaccination with several TUMAPs simultaneously triggers a broad immune attack against the tumor.

Figure 2.

Selection, Identification and Validation of TUMAPs.

Figure 3.

Local injection site reactions i.e., erythema, induration, edema, itching and pain 5 minutes and 24 hours post vaccination and about 1 month after last vaccination. (Safety population; N = 30).

Figure 4.

Waterfall plot and vaccine-induced T-cell responses as indicated by the TUMAPs named above the bar representing the percentage of change in longest diameter of target lesions. The occurrence of new lesions is outlined and patients without measurable disease according to RECIST at baseline are marked with a shadow around the zero. Patient numbers and the treatment line of the vaccination therapy are illustrated.

Figure 5.

Association between vaccine-induced T-cell responses and clinical benefit defined as responding or stable disease after 3 months of vaccination (at the follow up visit). The clinical benefit rates were 14%, 33% and 75% for patients with 0, 1 and ≥ 2 TUMAP responses, respectively. 38% of Non-HBV responders and 47% of HBV responders had their disease controlled at the follow up visit.

Figure 6.

Association between pre-vaccination Treg frequency and number of induced TUMAP responses (n = 26). Lower pre-vaccination frequencies of Treg cells defined as CD4+Foxp3+ cells among CD45+ lymphocytes (y axis) were associated with the induction of multiple IMA901 TUMAP responses (x axis). Every dot represents one patient and horizontal lines illustrate the median Treg frequencies.

Figure 7.

OS and PFS of patients treated in the phase II study (per protocol population). (a) PFS of patients pre-treated with cyclophosphamide or without such pre-treatment. (b) OS of patients pre-treated with cyclophosphamide or without such pre-treatment. (c) OS of patients evaluable for immune responses in the following groups: immune responders pre-treated with cyclophosphamide, +Cy ≥ 1; patients pre-treated with cyclophosphamide for whom no immune response was observed, +Cy 0; immune responders without cyclophosphamide pre-treatment, −Cy ≥ 1; patients without cyclophosphamide pre-treatment for whom no immune response was observed, −Cy 0. (d) OS of patients for whom no immune response was observed, immune responders to one TUMAP, immune responders to 2 TUMAPs or immune responders to at least 3 TUMAPs.